2022

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21 pages, 7852 KiB

Open AccessArticle

Lipid Peroxides Mediated Ferroptosis in Electromagnetic Pulse-Induced Hippocampal Neuronal Damage via Inhibition of GSH/GPX4 Axis

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Int. J. Mol. Sci. 2022, 23(16), 9277; https://doi.org/10.3390/ijms23169277 - 17 Aug 2022

Cited by 4 | Viewed by 1794

Abstract

Electromagnetic pulse (EMP) radiation was reported to be harmful to hippocampal neurons. However, the mechanism underlying EMP-induced neuronal damage remains unclear. In this paper, for the first time, we attempted to investigate the involvement of ferroptosis in EMP-induced neuronal damage and its underlying [...] Read more.

Electromagnetic pulse (EMP) radiation was reported to be harmful to hippocampal neurons. However, the mechanism underlying EMP-induced neuronal damage remains unclear. In this paper, for the first time, we attempted to investigate the involvement of ferroptosis in EMP-induced neuronal damage and its underlying mechanism. In vivo studies were conducted with a rat model to examine the association of ferroptosis and EMP-induced hippocampal neuronal damage. Moreover, in vitro studies were conducted with HT22 neurons to investigate the underlying mechanism of EMP-induced neuronal ferroptosis. In vivo results showed that EMP could induce learning and memory impairment of rats, ferroptotic morphological damages to mitochondria, accumulation of malonaldehyde (MDA) and iron, overexpression of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA, and downregulation of GPX4 protein in rat hippocampus. In vitro results showed that EMP could induce neuronal death, MDA accumulation, iron overload, PTGS2 overexpression, and GPX4 downregulation in HT22 neurons. These adverse effects could be reversed by either lipid peroxides scavenger ferrostatin-1 or overexpression of GPX4. These results suggest that EMP radiation can induce ferroptosis in hippocampal neurons via a vicious cycle of lipid peroxides accumulation and GSH/GPX4 axis downregulation. Lipid peroxides and the GSH/GPX4 axis provide potential effective intervention targets to EMP-induced hippocampal neuronal damage. Full article

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2021

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14 pages, 3271 KiB

Open AccessArticle

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Kota Sato

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Soichiro Iwasaki

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Hironori Yoshino

Int. J. Mol. Sci. 2021, 22(24), 13233; https://doi.org/10.3390/ijms222413233 - 08 Dec 2021

Cited by 3 | Viewed by 3855

Abstract

Senolytic agents eliminate senescent cells and are expected to reduce senescent cell-mediated adverse effects in cancer therapy. However, the effects of senolytic agents on the survival of irradiated cancer cells remain unknown. Here, the effects of the senolytic agent ABT-263 on the survival [...] Read more.

Senolytic agents eliminate senescent cells and are expected to reduce senescent cell-mediated adverse effects in cancer therapy. However, the effects of senolytic agents on the survival of irradiated cancer cells remain unknown. Here, the effects of the senolytic agent ABT-263 on the survival of irradiated A549 and Ca9-22 cancer cells were investigated. ABT-263 was added to the culture medium after irradiation. SA-β-gal activity and cell size, which are hallmarks of cell senescence, were evaluated using a flow cytometer. The colony-forming assay and annexin V staining were performed to test cell survival. We first confirmed that radiation increased the proportion of cells with high SA-β-gal activity and that ABT-263 decreased it. Of note, ABT-263 decreased the survival of irradiated cancer cells and increased the proportion of radiation-induced annexin V⁺ cells. Furthermore, the caspase inhibitor suppressed the ABT-263-induced decrease in the survival of irradiated cells. Intriguingly, ABT-263 decreased the proportion of SA-β-gal low-activity/large cells in the irradiated A549 cells, which was recovered by the caspase inhibitor. Together, these findings suggest that populations maintaining the ability to proliferate existed among the irradiated cancer cells showing senescence-related features and that ABT-263 eliminated the population, which led to decreased survival of irradiated cancer cells. Full article

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15 pages, 29622 KiB

Open AccessArticle

The Effects of Melatonin Administration on Intestinal Injury Caused by Abdominal Irradiation from Mice

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Int. J. Mol. Sci. 2021, 22(18), 9715; https://doi.org/10.3390/ijms22189715 - 08 Sep 2021

Cited by 5 | Viewed by 1903

Abstract

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the [...] Read more.

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms. Full article

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13 pages, 2613 KiB

Open AccessArticle

DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells

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Int. J. Mol. Sci. 2021, 22(1), 420; https://doi.org/10.3390/ijms22010420 - 03 Jan 2021

Cited by 9 | Viewed by 3217

Abstract

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than [...] Read more.

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression. Full article

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2020

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12 pages, 1532 KiB

Open AccessBrief Report

Geomagnetic Shielding Enhances Radiation Resistance by Promoting DNA Repair Process in Human Bronchial Epithelial Cells

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Int. J. Mol. Sci. 2020, 21(23), 9304; https://doi.org/10.3390/ijms21239304 - 06 Dec 2020

Cited by 7 | Viewed by 2195

Abstract

With the advent of long-duration space explorations, ionizing radiation (IR) may pose a constant threat to astronauts without the protection of Earth’s magnetic field, or hypomagnetic field (HMF). However, the potential biological effects of a HMF on the cellular response to IR have [...] Read more.

With the advent of long-duration space explorations, ionizing radiation (IR) may pose a constant threat to astronauts without the protection of Earth’s magnetic field, or hypomagnetic field (HMF). However, the potential biological effects of a HMF on the cellular response to IR have not been well characterized so far. In this study, immortalized human bronchial epithelial cells were exposed to X-rays under either a geomagnetic field (GMF, ~50 uT) or HMF (<50 nT) culture condition. A significant increase of the cell survival rate in HMF after radiation was observed by colony formation analysis. The kinetics of DNA double-strand breaks (DSBs), determined by γH2AX foci formation and disappearance, presented a faster decrease of foci-positive cells and a significantly lower mean number of γH2AX foci per nucleus in HMF-cultured cells than in GMF-cultured cells after radiation. In addition, a γH2AX/53BP1 colocalization assay showed an upregulated DSB recovery rate in HMF cultured cells. These findings provided the first evidence that HMF exposure may enhance the cellular DSB repair efficiency upon radiation, and consequently modulate the genotoxic effects of IR. Full article

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21 pages, 4060 KiB

Open AccessArticle

The p53–53BP1-Related Survival of A549 and H1299 Human Lung Cancer Cells after Multifractionated Radiotherapy Demonstrated Different Response to Additional Acute X-ray Exposure

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Margarita Pustovalova

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Roman Chuprov-Netochin

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Andreyan N. Osipov

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Sergey Leonov

Int. J. Mol. Sci. 2020, 21(9), 3342; https://doi.org/10.3390/ijms21093342 - 08 May 2020

Cited by 19 | Viewed by 4119

Abstract

Radiation therapy is one of the main methods of treating patients with non-small cell lung cancer (NSCLC). However, the resistance of tumor cells to exposure remains the main factor that limits successful therapeutic outcome. To study the molecular/cellular mechanisms of increased resistance of [...] Read more.

Radiation therapy is one of the main methods of treating patients with non-small cell lung cancer (NSCLC). However, the resistance of tumor cells to exposure remains the main factor that limits successful therapeutic outcome. To study the molecular/cellular mechanisms of increased resistance of NSCLC to ionizing radiation (IR) exposure, we compared A549 (p53 wild-type) and H1299 (p53-deficient) cells, the two NSCLC cell lines. Using fractionated X-ray irradiation of these cells at a total dose of 60 Gy, we obtained the survived populations and named them A549IR and H1299IR, respectively. Further characterization of these cells showed multiple alterations compared to parental NSCLC cells. The additional 2 Gy exposure led to significant changes in the kinetics of γH2AX and phosphorylated ataxia telangiectasia mutated (pATM) foci numbers in A549IR and H1299IR compared to parental NSCLC cells. Whereas A549, A549IR, and H1299 cells demonstrated clear two-component kinetics of DNA double-strand break (DSB) repair, H1299IR showed slower kinetics of γH2AX foci disappearance with the presence of around 50% of the foci 8 h post-IR. The character of H2AX phosphorylation in these cells was pATM-independent. A decrease of residual γH2AX/53BP1 foci number was observed in both A549IR and H1299IR compared to parental cells post-IR at extra doses of 2, 4, and 6 Gy. This process was accompanied with the changes in the proliferation, cell cycle, apoptosis, and the expression of ATP-binding cassette sub-family G member 2 (ABCG2, also designated as CDw338 and the breast cancer resistance protein (BCRP)) protein. Our study provides strong evidence that different DNA repair mechanisms are activated by multifraction radiotherapy (MFR), as well as single-dose IR, and that the enhanced cellular survival after MFR is reliant on both p53 and 53BP1 signaling along with non-homologous end-joining (NHEJ). Our results are of clinical significance as they can guide the choice of the most effective IR regimen by analyzing the expression status of the p53–53BP1 pathway in tumors and thereby maximize therapeutic benefits for the patients while minimizing collateral damage to normal tissue. Full article

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2019

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10 pages, 1185 KiB

Open AccessArticle

Laser-Driven Ultrashort Pulsed Electron Beam Radiation at Doses of 0.5 and 1.0 Gy Induces Apoptosis in Human Fibroblasts

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Margarita Pustovalova

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Anna Grekhova

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Andreyan N. Osipov

Int. J. Mol. Sci. 2019, 20(20), 5140; https://doi.org/10.3390/ijms20205140 - 17 Oct 2019

Cited by 17 | Viewed by 2888

Abstract

Rapidly evolving laser technologies have led to the development of laser-generated particle accelerators as an alternative to conventional facilities. However, the radiobiological characteristics need to be determined to enhance their applications in biology and medicine. In this study, the radiobiological effects of ultrashort [...] Read more.

Rapidly evolving laser technologies have led to the development of laser-generated particle accelerators as an alternative to conventional facilities. However, the radiobiological characteristics need to be determined to enhance their applications in biology and medicine. In this study, the radiobiological effects of ultrashort pulsed electron beam (UPEB) and X-ray radiation in human lung fibroblasts (MRC-5 cell line) exposed to doses of 0.1, 0.5, and 1 Gy are compared. The changes of γH2AX foci number as a marker of DNA double-strand breaks (DSBs) were analyzed. In addition, the micronuclei induction and cell death via apoptosis were studied. We found that the biological action of UPEB-radiation compared to X-rays was characterized by significantly slower γH2AX foci elimination (with a dose of 1 Gy) and strong apoptosis induction (with doses of 0.5 and 1.0 Gy), accompanied by a slight increase in micronuclei formation (dose of 1 Gy). Our data suggest that UPEB radiation produces more complex DNA damage than X-ray radiation, leading to cell death rather than cytogenetic disturbance. Full article

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12 pages, 3103 KiB

Open AccessArticle

Effect of Ionizing Radiation from Computed Tomography on Differentiation of Human Embryonic Stem Cells into Neural Precursors

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Int. J. Mol. Sci. 2019, 20(16), 3900; https://doi.org/10.3390/ijms20163900 - 10 Aug 2019

Cited by 3 | Viewed by 3321

Abstract

We studied the effect of radiation from computed tomography (CT) scans on differentiation of human embryonic stem cells (hESCs) into neuronal lineage. hESCs were divided into three radiation exposure groups: 0-dose, low-dose, or high-dose exposure. Low dose was accomplished with a single 15 [...] Read more.

We studied the effect of radiation from computed tomography (CT) scans on differentiation of human embryonic stem cells (hESCs) into neuronal lineage. hESCs were divided into three radiation exposure groups: 0-dose, low-dose, or high-dose exposure. Low dose was accomplished with a single 15 mGy CT dose index (CTDI) CT scan that approximated the dose for abdominal/pelvic CT examinations in adults while the high dose was achieved with several consecutive CT scans yielding a cumulative dose of 500 mGy CTDI. The neural induction was characterized by immunocytochemistry. Quantitative polymerase chain reaction (qPCR) and Western blots were used to measure expression of the neuronal markers PAX6 and NES and pluripotency marker OCT4. We did not find any visible morphological differences between neural precursors from irradiated and non-irradiated cells. However, quantitative analyses of neuronal markers showed that PAX6 expression was reduced following exposure to the high dose compared to 0-dose controls, while no such decrease in PAX6 expression was observed following exposure to the low dose. Similarly, a statistically significant reduction in expression of NES was observed following high-dose exposure, while after low-dose exposure, a modest but statistically significant reduction in NES expression was only observed on Day 8 of differentiation. Further studies are warranted to elucidate how lower or delayed expression of PAX6 and NES can impact human fetal brain development. Full article

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13 pages, 1177 KiB

Open AccessCommunication

Formation of γH2AX and pATM Foci in Human Mesenchymal Stem Cells Exposed to Low Dose-Rate Gamma-Radiation

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Stepan Ulyanenko

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Margarita Pustovalova

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Int. J. Mol. Sci. 2019, 20(11), 2645; https://doi.org/10.3390/ijms20112645 - 29 May 2019

Cited by 26 | Viewed by 4111

Abstract

DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in [...] Read more.

DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in human stem cells. The aim of this study was to examine the formation of DSB markers (γH2AX and phosphorylated kinase ATM, pATM, foci) in human mesenchymal stem cells (MSCs) exposed to chronic gamma-radiation (0.1 mGy/min) in comparison with acute irradiation (30 mGy/min) at cumulative doses of 30, 100, 160, 240 and 300 mGy. A linear dose-dependent increase in the number of both γH2AX and pATM foci, as well as co-localized γH2AX/pATM foci (“true” DSB), were observed after an acute radiation exposure. In contrast, the response of MSCs to a chronic low dose-rate IR exposure deviated from linearity towards a threshold model, for γH2AX, pATM foci and γH2AX/pATM foci, with an indication of a “plateau”. The state of equilibrium between newly formed DSB at a low rate during the protracted exposure time and the elimination of a fraction of DSB is proposed as a mechanistic explanation of the non-linear DSB responses following a low dose-rate irradiation. This notion is supported by the observation of the elimination of a substantial fraction of DSB 6 h after the cessation of the exposures. Our results demonstrate non-linear dose responses for γH2AX and pATM foci in human MSCs exposed to low dose-rate IR and showed the existence of a threshold, which may have implications for radiation protection in humans. Full article

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20 pages, 5813 KiB

Open AccessArticle

Bone Marrow Endothelial Cells Influence Function and Phenotype of Hematopoietic Stem and Progenitor Cells after Mixed Neutron/Gamma Radiation

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Int. J. Mol. Sci. 2019, 20(7), 1795; https://doi.org/10.3390/ijms20071795 - 11 Apr 2019

Cited by 8 | Viewed by 3928

Abstract

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the [...] Read more.

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the BM. Damage to this niche upon exposure to ionizing radiation, whether accidental or as a result of therapy, can contribute to delays in HSC recovery and/or function. The ability of BM derived-endothelial cells (BMEC) to alter and/or protect HSPC after exposure to ionizing radiation was investigated. Our data show that exposure of BMEC to ionizing radiation resulted in alterations in Akt signaling, increased expression of PARP-1, IL6, and MCP-1, and decreased expression of MMP1 and MMP9. In addition, global analysis of gene expression of HSC and BMEC in response to mixed neutron/gamma field (MF) radiation identified 60 genes whose expression was altered after radiation in both cell types, suggesting that a subset of genes is commonly affected by this type of radiation. Focused gene analysis by RT-PCR revealed two categories of BMEC alterations: (a) a subset of genes whose expression was altered in response to radiation, with no additional effect observed during coculture with HSPC, and (b) a subset of genes upregulated in response to radiation, and altered when cocultured with HSPC. Coculture of BMEC with CD34+ HSPC induced HSPC proliferation, and improved BM function after MF radiation. Nonirradiated HSPC exhibited reduced CD34 expression over time, but when irradiated, they maintained higher CD34 expression. Nonirradiated HSPC cocultured with nonirradiated BMEC expressed lower levels of CD34 expression compared to nonirradiated alone. These data characterize the role of each cell type in response to MF radiation and demonstrate the interdependence of each cell’s response to ionizing radiation. The identified genes modulated by radiation and coculture provide guidance for future experiments to test hypotheses concerning specific factors mediating the beneficial effects of BMEC on HSPC. This information will prove useful in the search for medical countermeasures to radiation-induced hematopoietic injury. Full article

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2018

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14 pages, 2245 KiB

Open AccessArticle

Melatonin Sensitizes Human Colorectal Cancer Cells to γ-ray Ionizing Radiation In Vitro and In Vivo

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Int. J. Mol. Sci. 2018, 19(12), 3974; https://doi.org/10.3390/ijms19123974 - 10 Dec 2018

Cited by 27 | Viewed by 3925

Abstract

Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in [...] Read more.

Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in clinical radiobiology. However, resistance to radiotherapy for colorectal cancer greatly decreases the therapeutic outcome. Melatonin (N-acetyl-5-methoxytryptamine), a natural secretory product that the pineal gland in the brain normally produces, has been reported to have anticancer properties. In the study, we investigated the combination of melatonin with radiotherapy as a treatment for colorectal cancer. We firstly explored the anti-tumor activity of melatonin combined with ionizing radiation (IR) against colorectal carcinoma in vitro. It was found that melatonin effectively inhibited human colorectal carcinoma cell line HCT 116 cellular proliferation, colony formation rate and cell migration counts following IR. Increasing the radiosensitivity of colorectal cancer cells by melatonin treatment was found to be associated with cell cycle arrest in the G2/M phase, downregulation of proteins involved in DNA double-strand break repair and activation of the caspase-dependent apoptotic pathway. Moreover, we also investigated the combined effect of IR and melatonin on colorectal tumor in vivo. Results from a tumor xenograft showed that melatonin plus IR treatment significantly suppressed tumor cell growth compared with melatonin or IR alone, resulting in a much higher tumor inhibition rate for the combined treatment. The data suggested that melatonin combined with IR could improve the radiosensitivity of colorectal cancer and thus enhance the therapeutic effect of the patients, implying melatonin could function as a potential sensitizer in tumor radiotherapy. Full article

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17 pages, 3415 KiB

Open AccessArticle

Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages

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Int. J. Mol. Sci. 2018, 19(10), 3154; https://doi.org/10.3390/ijms19103154 - 13 Oct 2018

Cited by 9 | Viewed by 4527

Abstract

Radiosensitivity varies depending on the cell type; highly differentiated cells typically exhibit greater radioresistance. We recently demonstrated that human macrophages derived from THP-1 monocytic cells, which lack TP53, are highly resistant to radiation-induced apoptosis compared with undifferentiated THP-1 cells. However, the mechanisms [...] Read more.

Radiosensitivity varies depending on the cell type; highly differentiated cells typically exhibit greater radioresistance. We recently demonstrated that human macrophages derived from THP-1 monocytic cells, which lack TP53, are highly resistant to radiation-induced apoptosis compared with undifferentiated THP-1 cells. However, the mechanisms by which THP-1 cells acquire radioresistance during differentiation remain unknown. Herein, we investigated the mechanisms by which THP-1-derived macrophages develop p53-independent radioresistance by analyzing DNA damage responses and apoptotic pathways. Analysis of γ-H2AX foci, which indicates the formation of DNA double-strand breaks (DSB), suggested that a capacity to repair DSB of macrophages is comparable to that of radiosensitive THP-1 cells. Furthermore, treatment with inhibitors against DSB repair-related proteins failed to enhance radiation-induced apoptosis in THP-1-derrived macrophages. Analysis of the apoptotic pathways showed that radiosensitive THP-1 cells undergo apoptosis through the caspase-8/caspase-3 cascade after irradiation, whereas this was not observed in the macrophages. Caspase-8 protein expression was lower in macrophages than in THP-1 cells, whereas mRNA expressions were comparable between both cell types. Co-treatment with a proteasome inhibitor and ionizing radiation effectively induced apoptosis in macrophages in a caspase-8-dependent manner. Results suggest that the regulation of caspase-8-mediated apoptosis during differentiation plays a role in the p53-independent radioresistance of THP-1-derived macrophages. Full article

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13 pages, 2832 KiB

Open AccessArticle

Oridonin Enhances Radiation-Induced Cell Death by Promoting DNA Damage in Non-Small Cell Lung Cancer Cells

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Int. J. Mol. Sci. 2018, 19(8), 2378; https://doi.org/10.3390/ijms19082378 - 13 Aug 2018

Cited by 24 | Viewed by 4237

Abstract

Although many attempts have been made to improve the efficacy of radiotherapy to treat cancer, radiation resistance is still an obstacle in lung cancer treatment. Oridonin is a natural compound with promising antitumor efficacy that can trigger cancer cell death; however, its direct [...] Read more.

Although many attempts have been made to improve the efficacy of radiotherapy to treat cancer, radiation resistance is still an obstacle in lung cancer treatment. Oridonin is a natural compound with promising antitumor efficacy that can trigger cancer cell death; however, its direct cellular targets, efficacy as a radiosensitizer, and underlying mechanisms of activity remain unclear. Herein, we report that oridonin exhibits additive cytotoxic and antitumor activity with radiation using the H460 non-small cell lung cancer cell lines. We assessed the effect of oridonin by proliferation, clonogenic, reactive oxygen species (ROS) production, DNA damage, and apoptosis assays. In vitro, oridonin enhanced the radiation-induced inhibition of cell growth and clonogenic survival. Oridonin also facilitated radiation-induced ROS production and DNA damage and enhanced apoptotic cell death. In vivo, the combination of oridonin and radiation effectively inhibited H460 xenograft tumor growth, with higher caspase-3 activation and H2A histone family member X (H2AX) phosphorylation compared with that of radiation alone. Our findings suggest that oridonin possesses a novel mechanism to enhance radiation therapeutic responses by increasing DNA damage and apoptosis. In conclusion, oridonin may be a novel small molecule to improve radiotherapy in non-small cell lung cancer. Full article

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2017

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897 KiB

Open AccessReview

Molecular Pathogenesis of Radiation-Induced Cell Toxicity in Stem Cells

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Wonhee Hur

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Seung Kew Yoon

Int. J. Mol. Sci. 2017, 18(12), 2749; https://doi.org/10.3390/ijms18122749 - 18 Dec 2017

Cited by 26 | Viewed by 13772

Abstract

Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances [...] Read more.

Radiation therapy is an effective cancer therapy, but damage to normal tissues surrounding the tumor due to radiotherapy causes severe complications. The importance of the therapeutic area between tumor suppression and normal tissue injury has long been highlighted in radiation therapy. Recent advances in stem cell biology have shown that stem cell (SC) responses to genotoxic stresses of ionizing radiation can improve the therapeutic effect of radiation by repairing damaged cells. In contrast, cancer stem cells (CSCs), a small subpopulation of cells within tumors, are generally resistant to chemotherapy and radiotherapy and cause tumor recurrence. Although the underlying mechanisms are not clearly understood in detail, efforts are still underway to identify SC treatment or CSC resistant pathogenesis of DNA damage agents such as radiation therapy. In response to radiation, CSCs differ from normal SCs in their biological properties due to severe deregulation of the self-renewal ability in CSCs. Differences of cleavage mode, cell cycle characteristics, replication potential, and activation/inactivation of DNA damage treatment and cancer-specific molecular pathways between normal SCs and CSCs confer a malignant phenotype upon CSCs. However, further studies are needed to identify normal SC and CSC-specific targets. In this review, we summarize the current advances in research regarding how normal SCs and CSCs respond to ionizing radiation, with a special emphasis on cell toxicity, radiosensitivity, signaling networks, DNA damage response (DDR) and DNA repair. In addition, we discuss strategies to develop new diagnostic and therapeutic techniques for predicting responses to cancer treatment and overcoming radiation-related toxicity. Full article

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3627 KiB

Open AccessArticle

Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose–Delivery and Dose–Response Study in Pigmented Hairless Mice

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Int. J. Mol. Sci. 2017, 18(12), 2738; https://doi.org/10.3390/ijms18122738 - 16 Dec 2017

Cited by 7 | Viewed by 4057

Abstract

Cumulative lifetime ultraviolet radiation (UVR) is an important factor in the development of squamous cell carcinoma. This study examines the impact of UVR exposure pattern on tumor development. Hairless C3.Cg/TifBomTac immunocompetent pigmented mice (n = 351) were irradiated with 12 standard erythema [...] Read more.

Cumulative lifetime ultraviolet radiation (UVR) is an important factor in the development of squamous cell carcinoma. This study examines the impact of UVR exposure pattern on tumor development. Hairless C3.Cg/TifBomTac immunocompetent pigmented mice (n = 351) were irradiated with 12 standard erythema doses (SED)/week, given as 2 SED ×6, 3 SED ×4, 4 SED ×3, or 6 SED ×2 (dose–delivery study) or 0, 0.6, 1.2, 2, 3 or 4 SED ×3/week (dose–response study). All mice were irradiated until development of 3 tumors of 4 mm each. Pigmentation was measured once monthly. In the dose–delivery study, the median time until tumor development was independent of dose fractions. In the dose–response study, higher UVR doses resulted in faster tumor appearance. When the weekly UVR dose was decreased from 12 to 6 SED, the cumulative UVR dose needed for tumor development was reduced by 40%. In conclusion, delivery schedules of a fixed weekly UVR dose did not affect tumor development. When using different weekly UVR doses, longer time to tumor development was observed using lower UVR doses. Lower weekly UVR doses however resulted in lower cumulative UVR doses to induce tumors in hairless pigmented mice. Full article

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299 KiB

Open AccessReview

Pharmacological Modulation of Radiation Damage. Does It Exist a Chance for Other Substances than Hematopoietic Growth Factors and Cytokines?

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Michal Hofer

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Zuzana Hoferová

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Martin Falk

Int. J. Mol. Sci. 2017, 18(7), 1385; https://doi.org/10.3390/ijms18071385 - 28 Jun 2017

Cited by 23 | Viewed by 4403

Abstract

In recent times, cytokines and hematopoietic growth factors have been at the center of attention for many researchers trying to establish pharmacological therapeutic procedures for the treatment of radiation accident victims. Two granulocyte colony-stimulating factor-based radiation countermeasures have been approved for the treatment [...] Read more.

In recent times, cytokines and hematopoietic growth factors have been at the center of attention for many researchers trying to establish pharmacological therapeutic procedures for the treatment of radiation accident victims. Two granulocyte colony-stimulating factor-based radiation countermeasures have been approved for the treatment of the hematopoietic acute radiation syndrome. However, at the same time, many different substances with varying effects have been tested in animal studies as potential radioprotectors and mitigators of radiation damage. A wide spectrum of these substances has been studied, comprising various immunomodulators, prostaglandins, inhibitors of prostaglandin synthesis, agonists of adenosine cell receptors, herbal extracts, flavonoids, vitamins, and others. These agents are often effective, relatively non-toxic, and cheap. This review summarizes the results of animal experiments, which show the potential for some of these untraditional or new radiation countermeasures to become a part of therapeutic procedures applicable in patients with the acute radiation syndrome. The authors consider β-glucan, 5-AED (5-androstenediol), meloxicam, γ-tocotrienol, genistein, IB-MECA (N⁶-(3-iodobezyl)adenosine-5’-N-methyluronamide), Ex-RAD (4-carboxystyryl-4-chlorobenzylsulfone), and entolimod the most promising agents, with regards to their contingent use in clinical practice. Full article

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Open AccessArticle

Pre-Exposure Gene Expression in Baboons with and without Pancytopenia after Radiation Exposure

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Int. J. Mol. Sci. 2017, 18(3), 541; https://doi.org/10.3390/ijms18030541 - 02 Mar 2017

Cited by 19 | Viewed by 4458

Abstract

Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons (n = 17) who developed haematologic acute radiation syndrome (HARS) without pancytopenia or a more aggravated HARS with pancytopenia after irradiation. [...] Read more.

Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons (n = 17) who developed haematologic acute radiation syndrome (HARS) without pancytopenia or a more aggravated HARS with pancytopenia after irradiation. We evaluated gene expression in a two stage study design where stage I comprised a whole genome screen for messenger RNAs (mRNA) (microarray) and detection of 667 microRNAs (miRNA) (real-time quantitative polymerase chain reaction (qRT-PCR) platform). Twenty candidate mRNAs and nine miRNAs were selected for validation in stage II (qRT-PCR). None of the mRNA species could be confirmed during the validation step, but six of the nine selected candidate miRNA remained significantly different during validation. In particular, miR-425-5p (receiver operating characteristic = 0.98; p = 0.0003) showed nearly complete discrimination between HARS groups with and without pancytopenia. Target gene searches of miR-425-5p identified new potential mRNAs and associated biological processes linked with radiosensitivity. We found that one miRNA species examined in pre-exposure blood samples was associated with HARS characterized by pancytopenia and identified new target mRNAs that might reflect differences in radiosensitivity of irradiated normal tissue. Full article

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2016

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Open AccessArticle

Development of Orally Administered γ-Tocotrienol (GT3) Nanoemulsion for Radioprotection

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Demaurian M. Mitchner

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Int. J. Mol. Sci. 2017, 18(1), 28; https://doi.org/10.3390/ijms18010028 - 24 Dec 2016

Cited by 13 | Viewed by 4928

Abstract

The purpose of this study was two-fold: (1) to formulate γ-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. γ-tocotrienol [...] Read more.

The purpose of this study was two-fold: (1) to formulate γ-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. γ-tocotrienol was incorporated into a nanoemulsion and lyophilized with lactose. Ultra performance liquid chromatography–mass spectroscopy (UPLC–MS) was used to monitor the chemical stability of GT3 over time, the particle size and ζ potential, and scanning electron microscopy (SEM) were used to study the physical stability of the nanoemulsion. Radioprotective and toxicity studies were performed in mice. The liquid formulation exhibited GT3 degradation at all storage temperatures. Lyophilization, in the presence of lactose, significantly reduced GT3 degradation. Both the liquid and lyophilized nanoemulsions had stable particle size and ζ potential when stored at 4 °C. Toxicity studies of the nanoemulsion resulted in no observable toxicity in mice at an oral dose of 600 mg/kg GT3. The nano-formulated GT3 (300 mg/kg) demonstrated enhanced survival efficacy compared to GT3 alone (200 and 400 mg/kg) in CD2F1 mice exposed to total body gamma radiation. The optimal long-term storage of formulated GT3 is as a powder at −20 °C to preserve drug and formulation integrity. Formulation of GT3 as a nanoemulsion for oral delivery as a prophylactic radioprotectant shows promise and warrants further investigation. Full article

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Open AccessArticle

Low Concentration of Exogenous Carbon Monoxide Modulates Radiation-Induced Bystander Effect in Mammalian Cell Cluster Model

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Int. J. Mol. Sci. 2016, 17(12), 2051; https://doi.org/10.3390/ijms17122051 - 08 Dec 2016

Cited by 4 | Viewed by 5967

Abstract

During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other [...] Read more.

During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO) was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2), at a relatively low concentration (20 µM), effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB) and micronucleus (MN). In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2) of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2) with a low concentration of 30 µM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1), MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX-2). The results can help mitigate RIBE-induced hazards during radiotherapy procedures. Full article

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Open AccessArticle

NOD Scid Gamma Mice Are Permissive to Allogeneic HSC Transplantation without Prior Conditioning

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Int. J. Mol. Sci. 2016, 17(11), 1850; https://doi.org/10.3390/ijms17111850 - 07 Nov 2016

Cited by 8 | Viewed by 5708

Abstract

Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development [...] Read more.

Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning. We transplanted allogeneic HSCs constitutively expressing the mCherry fluorescent marker into age-matched NSG mice and assessed donor chimerism 6 months post-transplantation. All transplanted NSG mice showed long-term myeloid and lymphoid cell chimerism. Also, in vivo irradiated HSCs showed long-term engraftment, although overall white blood cell (WBC) donor chimerism was lower compared with non-irradiated HSCs. Using this novel NSG transplantation model, we will be able to study the effects of low dose in vivo X-ray exposure on the long-term fate of HSCs, without the requirement of prior radio-ablation of the recipient, and thus leaving the recipient’s BM microenvironment uncompromised. In conclusion, we demonstrated for the first time that allogeneic HSCs from a different inbred strain can compete for niches in the BM compartment of NSG mice. Full article

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Open AccessReview

Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation

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Jeong-Min Park

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Tae-Hong Kang

Int. J. Mol. Sci. 2016, 17(11), 1840; https://doi.org/10.3390/ijms17111840 - 04 Nov 2016

Cited by 28 | Viewed by 7089

Abstract

Ultraviolet (UV) radiation from sunlight represents a constant threat to genome stability by generating modified DNA bases such as cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PP). If unrepaired, these lesions can have deleterious effects, including skin cancer. Mammalian cells are able [...] Read more.

Ultraviolet (UV) radiation from sunlight represents a constant threat to genome stability by generating modified DNA bases such as cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PP). If unrepaired, these lesions can have deleterious effects, including skin cancer. Mammalian cells are able to neutralize UV-induced photolesions through nucleotide excision repair (NER). The NER pathway has multiple components including seven xeroderma pigmentosum (XP) proteins (XPA to XPG) and numerous auxiliary factors, including ataxia telangiectasia and Rad3-related (ATR) protein kinase and RCC1 like domain (RLD) and homologous to the E6-AP carboxyl terminus (HECT) domain containing E3 ubiquitin protein ligase 2 (HERC2). In this review we highlight recent data on the transcriptional and posttranslational regulation of NER activity. Full article

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Open AccessArticle

Dose and Radioadaptive Response Analysis of Micronucleus Induction in Mouse Bone Marrow

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Chantal L. A. Brideau

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Mandy L. Serran

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Dmitry Y. Klokov

Int. J. Mol. Sci. 2016, 17(9), 1548; https://doi.org/10.3390/ijms17091548 - 13 Sep 2016

Cited by 15 | Viewed by 6290

Abstract

Enhanced cellular DNA repair efficiency and suppression of genomic instability have been proposed as mechanisms underlying radio-adaptive responses following low-dose radiation exposures. We previously showed that low-dose γ irradiation does not generate radio-adaptation by lowering radiation-induced cytogenetic damage in mouse spleen. Since radiation [...] Read more.

Enhanced cellular DNA repair efficiency and suppression of genomic instability have been proposed as mechanisms underlying radio-adaptive responses following low-dose radiation exposures. We previously showed that low-dose γ irradiation does not generate radio-adaptation by lowering radiation-induced cytogenetic damage in mouse spleen. Since radiation may exert tissue-specific effects, we extended these results here by examining the effects of γ radiation on cytogenetic damage and proliferative index in bone marrow erythrocytes of C57BL/6 and BALB/c mice. In C57BL/6 mice, the induction of micronuclei in polychromatic erythrocytes (MN-PCE) was observed at radiation doses of 100 mGy and greater, and suppression of erythroblast maturation occurred at doses of >500 mGy. A linear dose–response relationship for MN-PCE frequencies in C57BL/6 mice was established for radiation doses between 100 mGy and 1 Gy, with departure from linearity at doses of >1 Gy. BALB/c mice exhibited increased MN-PCE frequencies above baseline following a 20 mGy radiation exposure but did not exhibit radio-sensitivity relative to C57BL/6 mice following 2 Gy exposure. Radio-adaptation of bone marrow erythrocytes was not observed in either strain of mice exposed to low-dose priming γ irradiation (single doses of 20 mGy or 100 mGy or multiple 20 mGy doses) administered at various times prior to acute 2 Gy irradiation, confirming the lack of radio-adaptive response for induction of cytogenetic damage or suppression or erythrocyte proliferation/maturation in bone marrow of these mouse strains. Full article

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Open AccessArticle

Brusatol Enhances the Radiosensitivity of A549 Cells by Promoting ROS Production and Enhancing DNA Damage

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Int. J. Mol. Sci. 2016, 17(7), 997; https://doi.org/10.3390/ijms17070997 - 24 Jun 2016

Cited by 81 | Viewed by 7620

Abstract

NF-E2-related factor 2 (Nrf2) has been identified as a master regulatory factor in the protection of cells from oxidative and electrophilic stress. However, overexpression of Nrf2 in lung cancer may cause chemoresistance, as well as radioresistance. In this study, we examined the relationship [...] Read more.

NF-E2-related factor 2 (Nrf2) has been identified as a master regulatory factor in the protection of cells from oxidative and electrophilic stress. However, overexpression of Nrf2 in lung cancer may cause chemoresistance, as well as radioresistance. In this study, we examined the relationship between radioresistance and Nrf2 protein levels in H1299, A549, and H460 cells, and finally chose the A549 cell line to continue with due to its strong radioresistance and high Nrf2 protein levels. We found that the Nrf2 inhibitor, brusatol, could prevent the increase and accumulation of Nrf2 after exposure to irradiation. Additionally, following treatment with 80 nM brusatol, A549 cells became sensitive to irradiation, suffering severe DNA damage. Combination treatment with brusatol and ionizing radiation (IR) can distinctly increase the level of reactive oxygen species in A549 cells, causing a 1.8-fold increase compared with the control, and a 1.4-fold increase compared with IR alone. In fact, in the treatment with both brusatol and IR, lung cancer cell proliferation is halted, gradually leading to cell death. Because Nrf2 is closely linked to DNA damage repair, inhibiting the function of Nrf2, as in brusatol treatment, may increase the DNA damage caused by radiotherapy or chemotherapy, possibly enhancing the efficacy of chemotherapeutic drugs. Our study is the first to demonstrate brusatol’s ability to enhance the responsiveness of lung cancer cells to irradiation, and its potential application as a natural sensitizer in radiotherapy. Full article

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Open AccessArticle

The Protective Effects of 5-Methoxytryptamine-α-lipoic Acid on Ionizing Radiation-Induced Hematopoietic Injury

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Int. J. Mol. Sci. 2016, 17(6), 935; https://doi.org/10.3390/ijms17060935 - 14 Jun 2016

Cited by 35 | Viewed by 5396

Abstract

Antioxidants are prospective radioprotectors because of their ability to scavenge radiation-induced reactive oxygen species (ROS). The hematopoietic system is widely studied in radiation research because of its high radiosensitivity. In the present study, we describe the beneficial effects of 5-methoxytryptamine-α-lipoic acid (MLA), which [...] Read more.

Antioxidants are prospective radioprotectors because of their ability to scavenge radiation-induced reactive oxygen species (ROS). The hematopoietic system is widely studied in radiation research because of its high radiosensitivity. In the present study, we describe the beneficial effects of 5-methoxytryptamine-α-lipoic acid (MLA), which was synthesized from melatonin and α-lipoic acid, against radiation-induced hematopoietic injury. MLA administration significantly enhanced the survival rate of mice after 7.2 Gy total body irradiation. The results showed that MLA not only markedly increased the numbers and clonogenic potential of hematopoietic cells but also decreased DNA damage, as determined by flow cytometric analysis of histone H2AX phosphorylation. In addition, MLA decreased the levels of ROS in hematopoietic cells by inhibiting NOX4 expression. These data demonstrate that MLA prevents radiation-induced hematopoietic syndrome by increasing the number and function of and by inhibiting DNA damage and ROS production in hematopoietic cells. These data suggest MLA is beneficial for the protection of radiation injuries. Full article

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Open AccessArticle

Induction of Lipocalin2 in a Rat Model of Lung Irradiation

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Int. J. Mol. Sci. 2016, 17(5), 637; https://doi.org/10.3390/ijms17050637 - 28 Apr 2016

Cited by 3 | Viewed by 5624

Abstract

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to [...] Read more.

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1β and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement. Full article

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Open AccessArticle

Starvation after Cobalt-60 γ-Ray Radiation Enhances Metastasis in U251 Glioma Cells by Regulating the Transcription Factor SP1

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Int. J. Mol. Sci. 2016, 17(4), 386; https://doi.org/10.3390/ijms17040386 - 05 Apr 2016

Cited by 9 | Viewed by 5245

Abstract

Radiation is of clinical importance during glioma therapy; however, vasculature damage is observed over the treatment course. This type of tissue damage might lead to starvation conditions, affecting tumor metastasis. To test this possibility, we compared starvation conditions in conjunction with radiation treatment [...] Read more.

Radiation is of clinical importance during glioma therapy; however, vasculature damage is observed over the treatment course. This type of tissue damage might lead to starvation conditions, affecting tumor metastasis. To test this possibility, we compared starvation conditions in conjunction with radiation treatment to monitor metastatic ability in the U251 glioma cell line. Transcriptome, western blot, and immunofluorescence analyses were used to measure the RNA and protein expression changes of the U251 cells after various treatments. We found that starvation combined with radiation treatment yielded the most significant expression changes in metastasis-related factors compared to that in the control groups. In addition, a metastasis assay was used to directly measure the metastatic ability of the treated cells, which confirmed that the U251 cells treated with starvation combined with radiation possessed the highest metastatic ability. Furthermore, bioinformatics analysis demonstrated that SP1 represented a common transcription factor associated with changes in metastasis-related factors. Blocking SP1 activity by an inhibitor suppressed the starvation-plus-radiation treatment-mediated enhancement of U251 cell metastasis. Our study provides the first evidence that starvation caused by radiation might play a significant role in enhancing the ability of the glioma cell line U251 to metastasize via regulation of the transcription factor SP1. Full article

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Open AccessArticle

Assessment of Radiation Induced Therapeutic Effect and Cytotoxicity in Cancer Patients Based on Transcriptomic Profiling

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Mohammed H. Al-Qahtani

Int. J. Mol. Sci. 2016, 17(2), 250; https://doi.org/10.3390/ijms17020250 - 19 Feb 2016

Cited by 13 | Viewed by 6606

Abstract

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and [...] Read more.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue. Full article

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Open AccessReview

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

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Int. J. Mol. Sci. 2016, 17(1), 102; https://doi.org/10.3390/ijms17010102 - 14 Jan 2016

Cited by 280 | Viewed by 15182

Abstract

During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells [...] Read more.

During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization. Full article

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Open AccessArticle

Effect of Chromatin Structure on the Extent and Distribution of DNA Double Strand Breaks Produced by Ionizing Radiation; Comparative Study of hESC and Differentiated Cells Lines

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Int. J. Mol. Sci. 2016, 17(1), 58; https://doi.org/10.3390/ijms17010058 - 02 Jan 2016

Cited by 20 | Viewed by 7320

Abstract

Chromatin structure affects the extent of DNA damage and repair. Thus, it has been shown that heterochromatin is more protective against DNA double strand breaks (DSB) formation by ionizing radiation (IR); and that DNA DSB repair may proceed differently in hetero- and euchromatin [...] Read more.

Chromatin structure affects the extent of DNA damage and repair. Thus, it has been shown that heterochromatin is more protective against DNA double strand breaks (DSB) formation by ionizing radiation (IR); and that DNA DSB repair may proceed differently in hetero- and euchromatin regions. Human embryonic stem cells (hESC) have a more open chromatin structure than differentiated cells. Here, we study the effect of chromatin structure in hESC on initial DSB formation and subsequent DSB repair. DSB were scored by comet assay; and DSB repair was assessed by repair foci formation via 53BP1 antibody staining. We found that in hESC, heterochromatin is confined to distinct regions, while in differentiated cells it is distributed more evenly within the nuclei. The same dose of ionizing radiation produced considerably more DSB in hESC than in differentiated derivatives, normal human fibroblasts; and one cancer cell line. At the same time, the number of DNA repair foci were not statistically different among these cells. We showed that in hESC, DNA repair foci localized almost exclusively outside the heterochromatin regions. We also noticed that exposure to ionizing radiation resulted in an increase in heterochromatin marker H3K9me3 in cancer HT1080 cells, and to a lesser extent in IMR90 normal fibroblasts, but not in hESCs. These results demonstrate the importance of chromatin conformation for DNA protection and DNA damage repair; and indicate the difference of these processes in hESC. Full article

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2015

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Open AccessReview

Global Gene Expression Alterations as a Crucial Constituent of Human Cell Response to Low Doses of Ionizing Radiation Exposure

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Mykyta Sokolov

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Ronald Neumann

Int. J. Mol. Sci. 2016, 17(1), 55; https://doi.org/10.3390/ijms17010055 - 31 Dec 2015

Cited by 45 | Viewed by 5370

Abstract

Exposure to ionizing radiation (IR) is inevitable to humans in real-life scenarios; the hazards of IR primarily stem from its mutagenic, carcinogenic, and cell killing ability. For many decades, extensive research has been conducted on the human cell responses to IR delivered at [...] Read more.

Exposure to ionizing radiation (IR) is inevitable to humans in real-life scenarios; the hazards of IR primarily stem from its mutagenic, carcinogenic, and cell killing ability. For many decades, extensive research has been conducted on the human cell responses to IR delivered at a low dose/low dose (LD) rate. These studies have shown that the molecular-, cellular-, and tissue-level responses are different after low doses of IR (LDIR) compared to those observed after a short-term high-dose IR exposure (HDIR). With the advent of high-throughput technologies in the late 1990s, such as DNA microarrays, changes in gene expression have also been found to be ubiquitous after LDIR. Very limited subset of genes has been shown to be consistently up-regulated by LDIR, including CDKN1A. Further research on the biological effects and mechanisms induced by IR in human cells demonstrated that the molecular and cellular processes, including transcriptional alterations, activated by LDIR are often related to protective responses and, sometimes, hormesis. Following LDIR, some distinct responses were observed, these included bystander effects, and adaptive responses. Changes in gene expression, not only at the level of mRNA, but also miRNA, have been found to crucially underlie these effects having implications for radiation protection purposes. Full article

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Open AccessArticle

Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

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Charlie Garnett-Benson

Int. J. Mol. Sci. 2015, 16(12), 30405-30421; https://doi.org/10.3390/ijms161226238 - 21 Dec 2015

Cited by 19 | Viewed by 5315

Abstract

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce [...] Read more.

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8⁺ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity. Full article

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Open AccessReview

Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

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Int. J. Mol. Sci. 2015, 16(12), 30309-30320; https://doi.org/10.3390/ijms161226234 - 18 Dec 2015

Cited by 11 | Viewed by 6487

Abstract

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ [...] Read more.

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies. Full article

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Open AccessArticle

Histone H2AX Is Involved in FoxO3a-Mediated Transcriptional Responses to Ionizing Radiation to Maintain Genome Stability

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Int. J. Mol. Sci. 2015, 16(12), 29996-30014; https://doi.org/10.3390/ijms161226216 - 16 Dec 2015

Cited by 12 | Viewed by 7353

Abstract

Histone H2AX plays a crucial role in molecular and cellular responses to DNA damage and in the maintenance of genome stability. It is downstream of ataxia telangiectasia mutated (ATM) damage signaling pathway and there is an emerging role of the transcription factor FoxO3a, [...] Read more.

Histone H2AX plays a crucial role in molecular and cellular responses to DNA damage and in the maintenance of genome stability. It is downstream of ataxia telangiectasia mutated (ATM) damage signaling pathway and there is an emerging role of the transcription factor FoxO3a, a regulator of a variety of other pathways, in activating this signaling. We asked whether H2AX may feedback to FoxO3a to affect respective FoxO3a-dependent pathways. We used a genetically matched pair of mouse embryonic fibroblast H2AX⁺^/+ and H2AX⁻^/− cell lines to carry out comprehensive time-course and dose-response experiments and to show that the expression of several FoxO3a-regulated genes was altered in H2AX⁻^/− compared to H2AX⁺^/+ cells at both basal and irradiated conditions. Hspa1b and Gadd45a were down-regulated four- to five-fold and Ddit3, Cdkn1a and Sod2 were up-regulated 2–3-fold in H2AX⁻^/− cells. Using the luciferase reporter assay, we directly demonstrated that transcriptional activity of FoxoO3a was reduced in H2AX⁻^/− cells. FoxO3a localization within the nuclear phospho-ATM (Ser1981) foci in irradiated cells was affected by the H2AX status, as well as its posttranslational modification (phospho-Thr32). These differences were associated with genomic instability and radiosensitivity in H2AX⁻^/− cells. Finally, knockdown of H2AX in H2AX⁺^/+ cells resulted in FoxO3a-dependent gene expression patterns and increased radiosensitivity that partially mimicked those found in H2AX⁻^/− cells. Taken together, our data suggest a role for FoxO3a in the maintenance of genome integrity in response to DNA damage that is mediated by H2AX via yet unknown mechanisms. Full article

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Open AccessArticle

Carbon Ion Irradiated Neural Injury Induced the Peripheral Immune Effects in Vitro or in Vivo

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Int. J. Mol. Sci. 2015, 16(12), 28334-28346; https://doi.org/10.3390/ijms161226109 - 30 Nov 2015

Cited by 17 | Viewed by 5657

Abstract

Carbon ion radiation is a promising treatment for brain cancer; however, the immune system involved long-term systemic effects evoke a concern of complementary and alternative therapies in clinical treatment. To clarify radiotherapy caused fundamental changes in peripheral immune system, examinations were performed based [...] Read more.

Carbon ion radiation is a promising treatment for brain cancer; however, the immune system involved long-term systemic effects evoke a concern of complementary and alternative therapies in clinical treatment. To clarify radiotherapy caused fundamental changes in peripheral immune system, examinations were performed based on established models in vitro and in vivo. We found that brain-localized carbon ion radiation of neural cells induced complex changes in the peripheral blood, thymus, and spleen at one, two, and three months after its application. Atrophy, apoptosis, and abnormal T-cell distributions were observed in rats receiving a single high dose of radiation. Radiation downregulated the expression of proteins involved in T-cell development at the transcriptional level and increased the proportion of CD3⁺CD4⁻CD8⁺ T-cells in the thymus and the proportion of CD3⁺CD4⁺CD8⁻ T-cells in the spleen. These data show that brain irradiation severely affects the peripheral immune system, even at relatively long times after irradiation. In addition, they provide valuable information that will implement the design of biological-based strategies that will aid brain cancer patients suffering from the long-term side effects of radiation. Full article

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Open AccessReview

Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

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Sona Balentova

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Marian Adamkov

Int. J. Mol. Sci. 2015, 16(11), 27796-27815; https://doi.org/10.3390/ijms161126068 - 24 Nov 2015

Cited by 101 | Viewed by 7502

Abstract

Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain [...] Read more.

Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors. Full article

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Open AccessArticle

Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

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Int. J. Mol. Sci. 2015, 16(11), 26249-26262; https://doi.org/10.3390/ijms161125953 - 03 Nov 2015

Cited by 21 | Viewed by 6354

Abstract

Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX [...] Read more.

Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC₅₀ values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC₅₀ values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer. Full article

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Open AccessArticle

A Co-Culture Model of Fibroblasts and Adipose Tissue-Derived Stem Cells Reveals New Insights into Impaired Wound Healing After Radiotherapy

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Int. J. Mol. Sci. 2015, 16(11), 25947-25958; https://doi.org/10.3390/ijms161125935 - 29 Oct 2015

Cited by 35 | Viewed by 6906

Abstract

External radiation seems to be associated with increased amounts of cytokines and other cellular modulators. Impaired microcirculation and fibrosis are examples of typical long term damage caused by radiotherapy. Adipose tissue-derived stem cells (ASC) are discussed to enhance wound healing, but their role [...] Read more.

External radiation seems to be associated with increased amounts of cytokines and other cellular modulators. Impaired microcirculation and fibrosis are examples of typical long term damage caused by radiotherapy. Adipose tissue-derived stem cells (ASC) are discussed to enhance wound healing, but their role in wounds due to radiotherapy is poorly understood. Normal human fibroblasts (NHF) and ASCs were co-cultured and external radiation with doses from 2–12 Gray (Gy) was delivered. Cell proliferation and mRNA levels of matrix metalloproteinases (MMP1, MMP2 and MMP13) were determined 48 h after irradiation of the co-cultures by qPCR. Additionally, tissue inhibitors of matrix metalloproteinases (TIMP1, TIMP2) were determined by enzyme-linked immunosorbent assay (ELISA). There was a reduction of cell proliferation after external radiation in mono-cultures of NHFs and ASCs compared to controls without irradiation. The co-culture of ASCs and NHFs showed reduced impairment of cell proliferation after external radiation. Gene expression of MMP1 and MMP13 was reduced after external irradiation in NHF. MMP2 expression of irradiated NHFs was increased. In the co-culture setting, MMP1 and MMP2 gene expression levels were upregulated. TIMP1 and TIMP2 protein expression was increased after irradiation in NHFs and their co-cultures with ASCs. ASCs seem to stimulate cell proliferation of NHFs and modulate relevant soluble mediators as well as proteinases after external radiation. Full article

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Open AccessArticle

TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells

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Nikolett Sándor

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Boglárka Schilling-Tóth

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Int. J. Mol. Sci. 2015, 16(10), 25450-25465; https://doi.org/10.3390/ijms161025450 - 23 Oct 2015

Cited by 9 | Viewed by 6760

Abstract

Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 [...] Read more.

Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts. Full article

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Open AccessArticle

Comparative Analysis of Whole-Genome Gene Expression Changes in Cultured Human Embryonic Stem Cells in Response to Low, Clinical Diagnostic Relevant, and High Doses of Ionizing Radiation Exposure

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Mykyta Sokolov

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Van Nguyen

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Ronald Neumann

Int. J. Mol. Sci. 2015, 16(7), 14737-14748; https://doi.org/10.3390/ijms160714737 - 30 Jun 2015

Cited by 10 | Viewed by 5041

Abstract

The biological effects of low-dose ionizing radiation (LDIR) exposure in humans are not comprehensively understood, generating a high degree of controversy in published literature. The earliest stages of human development are known to be among the most sensitive to stress exposures, especially genotoxic [...] Read more.

The biological effects of low-dose ionizing radiation (LDIR) exposure in humans are not comprehensively understood, generating a high degree of controversy in published literature. The earliest stages of human development are known to be among the most sensitive to stress exposures, especially genotoxic stresses. However, the risks stemming from exposure to LDIR, particularly within the clinical diagnostic relevant dose range, have not been directly evaluated in human embryonic stem cells (hESCs). Here, we describe the dynamics of the whole genome transcriptional responses of different hESC lines to both LDIR and, as a reference, high-dose IR (HDIR). We found that even doses as low as 0.05 Gy could trigger statistically significant transient changes in a rather limited subset of genes in all hESCs lines examined. Gene expression signatures of hESCs exposed to IR appear to be highly dose-, time-, and cell line-dependent. We identified 50 genes constituting consensus gene expression signature as an early response to HDIR across all lines of hESC examined. We observed substantial differences in biological pathways affected by either LDIR or HDIR in hESCs, suggesting that the molecular mechanisms underpinning the responses of hESC may fundamentally differ depending on radiation doses. Full article

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Open AccessArticle

The Effect of Diagnostic Absorbed Doses from ¹³¹I on Human Thyrocytes in Vitro

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Daria Orszulak-Michalak

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Int. J. Mol. Sci. 2015, 16(7), 14608-14622; https://doi.org/10.3390/ijms160714608 - 29 Jun 2015

Cited by 2 | Viewed by 4767

Abstract

Background: Administration of diagnostic activities of ¹³¹I, performed in order to detect thyroid remnants after surgery and/or thyroid cancer recurrence/metastases, may lead to reduction of iodine uptake. This phenomenon is called “thyroid stunning”. We estimated radiation absorbed dose-dependent changes in genetic material, [...] Read more.

Background: Administration of diagnostic activities of ¹³¹I, performed in order to detect thyroid remnants after surgery and/or thyroid cancer recurrence/metastases, may lead to reduction of iodine uptake. This phenomenon is called “thyroid stunning”. We estimated radiation absorbed dose-dependent changes in genetic material, in particular in sodium iodide symporter (NIS) gene promoter, and NIS protein level in human thyrocytes (HT). Materials and Methods: We used unmodified HT isolated from patients subjected to thyroidectomy exposed to ¹³¹I in culture. The different ¹³¹I activities applied were calculated to result in absorbed doses of 5, 10, and 20 Gy. Results: According to flow cytometry analysis and comet assay, ¹³¹I did not influence the HT viability in culture. Temporary increase of 8-oxo-dG concentration in HT directly after 24 h (p < 0.05) and increase in the number of AP-sites 72 h after termination of exposition to 20 Gy dose (p < 0.0001) were observed. The signs of dose-dependent DNA damage were not associated with essential changes in the NIS expression on mRNA and protein levels. Conclusions: Our observation constitutes a first attempt to evaluate the effect of the absorbed dose of ¹³¹I on HT. The results have not confirmed the theory that the “thyroid stunning” reduces the NIS protein synthesis. Full article

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Open AccessReview

Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging II: Over-Expression of Neprilysin Plays an Essential Role

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Genji Imokawa

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Hiroaki Nakajima

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Koichi Ishida

Int. J. Mol. Sci. 2015, 16(4), 7776-7795; https://doi.org/10.3390/ijms16047776 - 08 Apr 2015

Cited by 44 | Viewed by 10750

Abstract

Our previous studies strongly indicated that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Fortunately, we succeeded in identifying [...] Read more.

Our previous studies strongly indicated that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Fortunately, we succeeded in identifying human skin fibroblast-derived elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP). We have also characterized epithelial-mesenchymal paracrine cytokine interactions between UVB-exposed-keratinocytes and dermal fibroblasts and found that interleukin-1α and granulocyte macrophage colony stimulatory factor (GM-CSF) are intrinsic cytokines secreted by UVB-exposed keratinocytes that stimulate the expression of neprilysin by fibroblasts. On the other hand, direct UVA exposure of human fibroblasts significantly stimulates the secretion of IL-6 and also elicits a significant increase in the gene expression of matrix metallo-protease(MMP)-1 as well as neprilysin (to a lesser extent), which is followed by distinct increases in their protein and enzymatic activity levels. Direct UVA exposure of human keratinocytes also stimulates the secretion of IL-6, IL-8 and GM-CSF but not of IL-1 and endothelin-1. These findings suggest that GM-CSF secreted by UVA-exposed keratinocytes as well as IL-6 secreted by UVA-exposed dermal fibroblasts play important and additional roles in UVA-induced sagging and wrinkling by up-regulation of neprilysin and MMP-1, respectively, in dermal fibroblasts. Full article

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Open AccessReview

Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging I: Reduced Skin Elasticity, Highly Associated with Enhanced Dermal Elastase Activity, Triggers Wrinkling and Sagging

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Genji Imokawa

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Koichi Ishida

Int. J. Mol. Sci. 2015, 16(4), 7753-7775; https://doi.org/10.3390/ijms16047753 - 08 Apr 2015

Cited by 107 | Viewed by 14782

Abstract

The repetitive exposure of skin to ultraviolet B (UVB) preferentially elicits wrinkling while ultraviolet A (UVA) predominantly elicits sagging. In chronically UVB or UVA-exposed rat skin there is a similar tortuous deformation of elastic fibers together with decreased skin elasticity, whose magnitudes are [...] Read more.

The repetitive exposure of skin to ultraviolet B (UVB) preferentially elicits wrinkling while ultraviolet A (UVA) predominantly elicits sagging. In chronically UVB or UVA-exposed rat skin there is a similar tortuous deformation of elastic fibers together with decreased skin elasticity, whose magnitudes are greater in UVB-exposed skin than in UVA-exposed skin. Comparison of skin elasticity with the activity of matrix metalloproteinases (MMPs) in the dermis of ovariectomized rats after UVB or UVA irradiation demonstrates that skin elasticity is more significantly decreased in ovariectomized rats than in sham-operated rats, which is accompanied by a reciprocal increase in elastase activity but not in the activities of collagenases I or IV. Clinical studies using animal skin and human facial skin demonstrated that topical treatment with a specific inhibitor or an inhibitory extract of skin fibroblast-derived elastase distinctly attenuates UVB and sunlight-induced formation of wrinkling. Our results strongly indicated that the upregulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Full article

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Open AccessArticle

Protective Effects of Resveratrol against UVA-Induced Damage in ARPE19 Cells

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Int. J. Mol. Sci. 2015, 16(3), 5789-5802; https://doi.org/10.3390/ijms16035789 - 12 Mar 2015

Cited by 52 | Viewed by 8031

Abstract

Ultraviolet radiation, especially UVA, can penetrate the lens, reach the retina, and induce oxidative stress to retinal pigment epithelial (RPE) cells. Even though it is weakly absorbed by protein and DNA, it may trigger the production of reactive oxygen species (ROS) and generate [...] Read more.

Ultraviolet radiation, especially UVA, can penetrate the lens, reach the retina, and induce oxidative stress to retinal pigment epithelial (RPE) cells. Even though it is weakly absorbed by protein and DNA, it may trigger the production of reactive oxygen species (ROS) and generate oxidative injury; oxidative injury to the retinal pigment epithelium has been implicated to play a contributory role in age-related macular degeneration (AMD). Studies showed that resveratrol, an abundant and active component of red grapes, can protect several cell types from oxidative stress. In this study, adult RPE cells being treated with different concentrations of resveratrol were used to evaluate the protective effect of resveratrol on RPE cells against UVA-induced damage. Cell viability assay showed that resveratrol reduced the UVA-induced decrease in RPE cell viability. Through flow cytometry analysis, we found that the generation of intracellular H₂O₂ induced by UVA irradiation in RPE cells could be suppressed by resveratrol in a concentration-dependent manner. Results of Western blot analysis demonstrated that resveratrol lowered the activation of UVA-induced extracellular signal-regulated kinase, c-jun-NH₂ terminal kinase and p38 kinase in RPE cells. In addition, there was also a reduction in UVA-induced cyclooxygenase-2 (COX-2) expression in RPE cells pretreated with resveratrol. Our observations suggest that resveratrol is effective in preventing RPE cells from being damaged by UVA radiation, and is worth considering for further development as a chemoprotective agent for the prevention of early AMD. Full article

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2014

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Open AccessReview

Exposure to Non-Extreme Solar UV Daylight: Spectral Characterization, Effects on Skin and Photoprotection

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Claire Marionnet

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Caroline Tricaud

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Françoise Bernerd

Int. J. Mol. Sci. 2015, 16(1), 68-90; https://doi.org/10.3390/ijms16010068 - 23 Dec 2014

Cited by 115 | Viewed by 12238

Abstract

The link between chronic sun exposure of human skin and harmful clinical consequences such as photo-aging and skin cancers is now indisputable. These effects are mostly due to ultraviolet (UV) rays (UVA, 320–400 nm and UVB, 280–320 nm). The UVA/UVB ratio can vary [...] Read more.

The link between chronic sun exposure of human skin and harmful clinical consequences such as photo-aging and skin cancers is now indisputable. These effects are mostly due to ultraviolet (UV) rays (UVA, 320–400 nm and UVB, 280–320 nm). The UVA/UVB ratio can vary with latitude, season, hour, meteorology and ozone layer, leading to different exposure conditions. Zenithal sun exposure (for example on a beach around noon under a clear sky) can rapidly induce visible and well-characterized clinical consequences such as sunburn, predominantly induced by UVB. However, a limited part of the global population is exposed daily to such intense irradiance and until recently little attention has been paid to solar exposure that does not induce any short term clinical impact. This paper will review different studies on non-extreme daily UV exposures with: (1) the characterization and the definition of the standard UV daylight and its simulation in the laboratory; (2) description of the biological and clinical effects of such UV exposure in an in vitro reconstructed human skin model and in human skin in vivo, emphasizing the contribution of UVA rays and (3) analysis of photoprotection approaches dedicated to prevent the harmful impact of such UV exposure. Full article

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